RU2543325C2 - Using allopurinol for treating palmar-plantar erythrodysesthesia syndrome - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the pharmaceutical industry and represents a therapeutic agent used for treating or preventing palmar-plantar erythrodysesthesia syndrome (PPES) induced by a multifunction kinase inhibitor (MKI) therapy and containing a therapeutically effective amount of allopurinol or its pharmaceutically acceptable salt.

EFFECT: invention provides extending the range of products for treating or preventing palmar-plantar erythrodysesthesia syndrome (PPES) induced by the multifunction kinase inhibitor (MKI) therapy.

21 cl, 5 ex

Description

FIELD OF THE INVENTION

The present invention relates to the field of therapy, especially in oncology. It relates to the use of allopurinol or its pharmaceutically acceptable salts for the treatment or prevention of palmar plantar syndrome (LPS) caused by multipurpose kinase inhibitors (MICs). It also relates to methods for treating LPS.

BACKGROUND OF THE INVENTION

Malignant neoplasms are a group of diseases in which atypical cells are capable of uncontrolled division. Malignant cells can invade nearby tissues, and can spread through the bloodstream and lymphatic system to other parts of the body. There are several main types of malignant neoplasms. A carcinoma is a malignant neoplasm that develops in the skin or in tissues that restrict or cover the internal organs. Sarcoma is a malignant neoplasm that develops in bone, cartilage, adipose tissue, muscle, blood vessels, or other connective or supporting tissues. Leukemia is a malignant neoplasm originating from hematopoietic tissue, such as bone marrow, and leading to the formation and entry into the bloodstream of a huge amount of atypical blood cells. Lymphoma and multiple myeloma are malignant neoplasms that develop from cells of the immune system.

With regard to malignant neoplasms, several treatment options are possible, including surgical treatment and radiation therapy for a localized disease, and drugs that kill cancer cells (chemotherapy). Chemotherapy plays a significant role in the treatment of malignant tumors, since it is necessary in the treatment of advanced stages of malignant neoplasms with distant metastases and often helps to reduce the volume of the tumor before surgery (neoadjuvant therapy). It is also used after operations or irradiation (adjuvant therapy) to destroy possible residual malignant cells or to prevent relapse of a malignant neoplasm.

Many anticancer drugs are created using various mechanisms of their action: the most commonly used are alkylating agents that directly affect DNA (such as cisplatin, carboplatin, oxaliplatin, busulfan, chlorambucil, cyclophosphamide, ifosfamide, dacarbazine); antimetabolites that interfere with the synthesis of DNA and RNA (such as 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine (ara-C), fludarabine); anthracyclines that inhibit enzymes involved in DNA replication (such as daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone); microtubule-destroying substances (taxanes, such as paclitaxel and docetaxel or vinca alkaloids, such as vinblastine, vincristine and vinorelbine); topoisomerase inhibitors (such as etoposide, doxorubicin, topotecan and irinotecan); hormone therapy agents (such as tamoxifen, flutamide); and recently targeted targeted agents (such as cetuximab and gefitinib EGFR inhibitors or imatinib protein tyrosine kinase inhibitor).

The development of chemotherapy in recent decades has significantly improved the treatment of malignant neoplasms, which has led to the effective cure of certain types of malignant neoplasms and improved survival or time to disease progression in other forms. Currently, most chemotherapeutic agents are administered intravenously; however, chemotherapeutic agents for oral administration are becoming increasingly common.

Unfortunately, most chemotherapeutic agents are not able to distinguish between malignant and healthy cells. Therefore, chemotherapy often damages normal organs and tissues of the body, which leads to complication of treatment or side effects. In addition to the difficulties caused, side effects can prevent doctors from following the prescribed dosage of chemotherapy, which reduces the likelihood of adequate treatment for malignant neoplasms. The most common side effects of chemotherapy are anemia, neutropenia, thrombocytopenia, fatigue, baldness, nausea and vomiting, inflammation of the mucous membranes and pain.

One of the side effects associated with certain chemotherapeutic agents, especially 5-fluorouracil and its prodrug capecitabine, is palmar-plantar erythrodysesthesia (LET), an erythematous rash on the palms and feet, also known as acral erythema (AE). LET is a characteristic and relatively frequent toxic reaction. It is a painful swelling and erythematous rash, localized on the palms and feet, often accompanied by a violation of sensitivity, usually in the form of a tingling sensation, and often associated with edema. The rash can become bullous and then exfoliate without scarring with a gradual increase in pain. Erythema can also appear in the area of the nail bed. As a rule, it is limited by arms and legs, while the hands are usually more affected than the legs.

Histological analysis of LET reveals moderate interstitial edema, diffuse necrotic and keratin-free keratinocytes and vacuolar degeneration of the basal layer. Intradermal changes in most cases include dilated blood vessels, swelling of the papillary layer and diffuse superficial perivascular lymphohistiocytic infiltration, detected to some extent in the epidermis.

LET is clearly different from other adverse skin reactions and is described in detail in Nagore E. et al., Am J. Clin. Dermatol. 2000, 1 (4), 225-234. Despite the frequency, the causes of its occurrence are largely unknown.

The advent of molecular targeted therapies in recent decades has changed the nature of the treatment of malignant tumors. Among the methods of targeted therapy of malignant neoplasms, the development of agents that suppress angiogenesis, a process by which new blood vessels are formed, is of great interest. The formation of tumor vessels can be stopped and even reversed by suppressing the activity of receptors, for example platelet growth factor (PDGFR) and vascular endothelial growth factor receptor (VEGFR), or by inhibiting the components of their signaling cascades. One of these targets is the universal cascade of mitogen-activated protein kinase (MAPK) and the Raf / MEK / ERK cascade, which also includes signal transmission via MAPK and controls the growth and survival of human tumors by regulating the angiogenic cascade. Solid tumors are often characterized by activating oncogenic mutations in Ras and / or over-activation of Raf-1 kinase, leading to disruption of signaling via the MAPK cascade and subsequent tumor cell proliferation and angiogenesis.

Such a reasonable approach to the treatment of malignant tumors leads to the development of the second generation of tyrosine kinase inhibitors, which are able to hit many targets or cascades. Extremely attractive are the means aimed at many cascades of tumor growth, potentially having the effects of combination therapy in one tool. Most of these novel agents inhibit more than one tyrosine kinase receptor and may have unique inhibition profiles. Among the multipurpose kinase inhibitors (MICs), sorafenib and sunitinib are already approved, while vandetanib, motesanib, ABT-869 and some other compounds are still under development.

Sorafenib (Nexavar®) is an oral medication that can suppress several tyrosine kinase receptors involved in tumor progression and angiogenesis. Sorafenib blocks Raf (serine-threonine kinase) gene products, including mutant B-Raf, along with platelet-derived growth factor-beta (PDGFR-β), FLt3, and vascular endothelial growth factor receptor 2 and 3 (VEGFR-2 and 3) . Sorafenib was approved by the FDA in 2005 and EMEA was approved in 2006 for the treatment of metastatic renal cell carcinoma and advanced stages of hepatic cell carcinoma.

Sunitinib (Sutent®) is also an oral drug, a multipurpose tyrosine kinase inhibitor that blocks VEGFR-1, 2 and 3, PDGFR-α and β, Ret, c-Kit and FLT ₃ . In 2006, it was approved by the FDA and EMEA for use in patients with gastrointestinal stromal tumors (GIST) who cannot tolerate or are immune to imatinib mesylate, as well as in patients with metastatic renal cell carcinoma. It is usually prescribed in 4-week courses with 2-week breaks in order to allow patients to recover from possible toxic effects.

MKIs, such as sorafenib and sunitinib, have side effects, the most common of which are fatigue, hypertension, nausea, and diarrhea. However, their level of safety is generally preferred over many standard chemotherapeutic agents.

However, like other tyrosine kinase inhibitors, MICs are associated with significant dermatological adverse reactions. Palmar-plantar syndrome (LPS) is the most clinically significant ( Rosenbaum SE et al. Support Care Cancer (2008) 16: 557-566 "Dermatological reactions to the multitargeted tyrosine kinase inhibitor sunitinib"; Robert C et al. J. Am Acad. Dermatol. 2009, vol. 60 no. 2, 299-305 "Dermatological symptoms associated with the multikinase inhibitor sorafenib" ).

Palmar-plantar syndrome (LPS) is a certain limited skin reaction, in particular on the palms and / or feet, characterized by erythema, numbness, tingling sensation and other dysesthesia or paresthesia. A histological examination is characterized by thickening, pronounced hyperkeratotic lesions, often affecting the joint areas of the fingers. It develops during the first 2-4 weeks after the appointment of the MIC. After a few weeks, lesions, with or without blisters, are supplemented by painful areas of thickening or hyperkeratosis of the skin, resembling calluses.

LPS is described in: Lacouture ME et al. The Oncologist 2008, 13, no. 9, 1001-1011: "Evolving Strategies for the management of Hand-Foot Skin Reaction associated with the Multitargeted Kinase Inhibitors Sorafenib and Sunitinib"; Beldner M et al. The Oncologist 2007 12: 1178-1182 "Localized Palmar-Plantar epidermal hyperplasia: a previously undefined dermatological toxicity to sorafenib"; Yang CH et al. British journal of Dermatology 2008, 158 592-596 "Hand-Foot skin reaction in patients treated with sorafenib: a clinopathological study of cutaneous manifestations due to multitargeted kinase inhibitor therapy"; Porta C et al. Clin Exp Med 2007, 7: 12-134 "Uncovering Pandora's vase: the growing problem of new toxicities from novel anticancer agents. The case of sorafenib and sunitinib"; Wood L. et al. Community Oncology 2010, vol. 7, no. 1 pages 23-29: "Practical Considerations in the Treatment of Hand Foot Skin Reaction caused by Multikinase Inhibitors . "

As indicated in these publications, the palm-plantar syndrome is clinically and histologically different from palmar-plantar erythrodysesthesia (LET) [also known as acne erythema (AE)], caused by chemotherapy, such as 5-FU, capecitabine, or pegylated liposomal doxorubicin.

Both conditions show palmar-plantar localization, sensory disturbances, soreness and a decrease in lesions after stopping the drug.

However, LPS and LET are distinguished by the typical picture of localized hyperkeratotic lesions surrounded by erythematous sites, in which there are symmetrical paresthesias, diffuse painful erythema and edema. Moreover, LPS can also affect non-working areas, such as the membranes between the fingers and toes and the side surfaces of the feet. In the pathogenetic aspect, MICs cause vacuolar degeneration of keratinocytes in a prickly layer together with epidermal acanthosis, while chemotherapy-induced LET shows inflammation at the border of the inner layer of the skin and epidermis, as well as vacuolar degeneration of basal keratinocytes. The main histological changes observed in LPS are considered to be a violation of cell maturation with deviations in the differentiation of keratinocytes, a possible increase in the level of apoptosis in this population of cells, as well as specific inflammation. With LPS, the rate of doubling of epidermal cells is significantly increased in places of active lesions. The main histopathological sign related to LPS is keratinocyte damage, which manifests itself in the form of intracellular eosinophilic bodies unique to this state. The mechanism of LPS is unknown.

The incidence of LPS is high. A meta-analysis showed that the total LPS rate in patients receiving sorafenib is 33.8% in stages 1-3 and 8.9% in stage 3 ( Chu D., Lacouture ME et al. Acta Oncologica 2008; 4 16-186: "Risk of Hand Foot Skin Reation with Sorafenib: A systematic Review and Meta-Analysis" ). For sunitinib, the total frequency is calculated as 18.9% in stages 1-3 and 5.5% in stage 3 ( Chu D. Lacouture ME, et al. Clinical Genitourinary Cancer 2009, no. 1 11-19: "Risk of Hand Foot Skin Reation with the Multitargeted Kinase Inhibitor Sunitinib in patients with Renal Cell and Non-Renal Cell carcinoma: a Meta-analysis " ). In patients receiving MIC, such as sorafenib and sunitinib, LPS can negatively affect normal quality of life and daily life.

The severity of LPS is a major component of the commonly used General Terminological Criteria for side effects of the National Cancer Institute (NCI-CTCAE v. 3.0). The clinical signs of each stage are:

1. Painless minimal skin changes or dermatitis (eg, erythema).

2. Skin changes (eg, peeling, blisters, bleeding, swelling) or pain; without disturbing the daily life of the patient;

3. Ulcerative dermatitis or painful skin changes; disrupt the daily life of the patient.

It can also be classified according to modified criteria that are more suitable for clinical practice ( Porta C et al. Clin Exp Med 2007, 7: 12-134 ):

1. Numbness, dysesthesia, paresthesia, tingling sensation, painless swelling, erythema or discomfort in the arms or legs that do not interfere with the normal functioning of the patient;

2. One or more of the following symptoms: painful erythema, swelling, hyperkeratosis of the hands or feet, discomfort that violates the normal functioning of the patient;

3. One or more of the following symptoms: wet peeling, ulceration, blistering, hyperkeratosis, severe pain in the arms and legs, severe discomfort that prevent the patient from working or carrying out daily activities.

There are currently no effective treatments for LPS. Before MIC therapy, it is recommended to eliminate existing hyperkeratotic patches and corns. If a skin reaction occurs after the start of MIC therapy, some of the following methods of treatment may be suggested: cold compresses or ice packs, avoid pressure on the arms or legs; skin hydration; emollient skin creams, clobetasol ointment, or local anesthetics. For more severe stages (2-3), a dose reduction or discontinuation of treatment with MICs is recommended. Creams containing urea, fluorouracil and tazarotene are also taken into account, since these agents inhibit the proliferation of keratinocytes ( Lacouture ME et al. The Oncologist 2008, vol. 13, no. 9, 1001-1011: "Evolving Strategies for the management of Hand- Foot Skin Reaction associated with the Multitargeted Kinase Inhibitors Sorafenib and Sunitinib ", Anderson et al. The Oncologist 2009, vol. 14, no. 3, 291-302:" Search for evidence-based approaches for the prevention and palliation of Hand-foot Skin Reaction (HFSR) caused by the Multikinase Inhibitors "); Wood L. et al. Community Oncology 2010, vol. 7, no. 1 opages 23-29: "Practical Considerations in the Treatment of Hand Foot Skin Reaction caused by Multikinase Inhibitors" ).

None of the currently proposed treatment methods can effectively treat or prevent LPS. This is a serious problem for the patient, since in addition to internal discomfort and pain, at advanced stages this leads to a decrease or discontinuation of chemotherapy via MIC, which negatively affects the survival and / or time until the progression of the malignant neoplasm during treatment. Obviously, it is still necessary to create an effective treatment for LPS in order to realize the full potential of multikinase inhibitors, various treatment regimens and combinations in which they can and will be used.

Allopurinol is a structural isomer of hypoxanthine; it inhibits xanthine oxidase, an enzyme that converts oxypurines to uric acid. By blocking the production of uric acid, this agent reduces the concentration of uric acid in serum and urine, thereby providing protection against terminal uric acid damage of organs in conditions associated with excessive production of uric acid. For many years, it has been used to treat or prevent gout, hyperuricemia and urolithiasis through oral or parenteral systemic administration.

The use of allopurinol for the treatment of mucositis has been shown to be widespread and caused by chemotherapy or radiation therapy for the defeat of rapidly dividing cells lining the oral cavity, pharynx and gastrointestinal tract (GIT). Allopurinol is used as mouthwashes (dispersions in water) ( Porta C. et al., Am J. Clin. Oncol. 1994, Vol 17, no.3, 246-247 ). An improved composition of mouthwashes including allopurinol, carboxymethyl cellulose and water is described in JP-3106817. Hanawa et al. Drug Dev Ind Pharm 2004, 30 (2) 151-161 describes another mouthwash including allopurinol, polyethylene oxide and carrageenan. Kitagawa et al. noted in J. Radiation Research 2008, vol. 49, no. 1, 49-54 , that the allopurinol gel reduces radiation-induced mucositis and dermatitis in rats. Dagher et al., Canadian Journal of Hospital Pharmacy, vol. 40, no.5 1987, page 189 , indicate the use of mouthwash with allopurinol and 0.1% vaginal cream for the treatment of mucositis caused by 5-FU.

Patents WO 94/05293 and WO 94/05291 describe synergistic compositions comprising methylsulfonylmethane (MSM) and at least one of oxypurinol or allopurinol and their use for treating skin conditions, diseases and injuries such as burns, dermatitis, hyperkeratosis , sun exposure, skin aging, etc. Oxypurinol and allopurinol are described as agents that enhance skin healing or restore the properties of MSM.

Patent WO 2007/138103 describes and contains examples of the use of allopurinol, in particular topically in the form of a cream for the treatment of palmar-plantar erythrodysesthesia or acne erythema caused by chemotherapy with fluoropyrimidine (5-FU and capecitabine). However, one skilled in the art knows that at the molecular level, fluoropyrimidine and multipurpose kinase inhibitors work by completely different mechanisms, and, as indicated above, their toxic effects on the skin differ both clinically and histologically.

In fact, an interdisciplinary team of specialists in Wood et al. (Community Oncology) on page 1 decided that:

"MIC-associated LPS is a toxic effect on the skin that is clinically and pathomorphologically different from AE observed with earlier chemotherapeutic agents."

None of the documents cited imply or suggest that allopurinol may be applicable for the treatment or prevention of palmar-plantar syndrome (LPS).

SUMMARY OF THE INVENTION

The inventor unexpectedly found that in the case of local application, especially on the palm and foot of the patient, allopurinol is extremely effective in the treatment and prevention of palmar-plantar syndrome (LPS) caused by multipurpose kinase inhibitors (MICs). As shown in the examples, the local use of allopurinol in patients with malignant neoplasms receiving MIC and having this developed condition leads to the complete disappearance of symptoms and prevents the further occurrence of LPS. This is more pronounced in the case of patients with LPS with typical developed hyperkeratosis, since it is expected that the local effect on the thick stratum corneum, located on the palms and feet, as well as the reversal of the process and the skin return to normal in a short period of time with the disappearance of hyperkeratosis, as shown in one example, it will be extremely difficult.

Thus, in one aspect, the invention relates to a medicament containing allopurinol or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of palmar-plantar syndrome caused by a multipurpose kinase inhibitor (MIC).

In a second aspect, the invention relates to the use of allopurinol or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of palmar-plantar syndrome caused by a multipurpose kinase inhibitor.

In a third aspect, the invention relates to a method for treating or preventing palmar-plantar syndrome caused by a multipurpose kinase inhibitor in a patient affected or predisposed to the condition, comprising topically applying a therapeutically effective amount of allopurinol or a pharmaceutically acceptable salt thereof.

Additional embodiments of the invention are defined in the claims.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "multipurpose tyrosine kinase receptor inhibitor" refers to a compound having a receptor binding profile exhibiting selectivity for many receptors for which an important role in the process of angiogenesis is shown.

In the context of the present invention, the term “palmar-plantar syndrome” (LPS) defines a side effect on the skin of the arms and legs of a patient with a malignant neoplasm receiving a multipurpose tyrosine kinase receptor inhibitor. Its clinical and histological features, as well as its stages, are described above. As explained, it differs from palmar-plantar erythrodysesthesia (LET), also known as acral erythema (AE), caused by other chemotherapeutic agents, such as 5-FU and capecitabine.

In the context of the present invention, the term "allopurinol" refers to various tautomeric compounds, as it is a tautomeric mixture of 1 H -pyrazolo- (3,4-d) -pyrimidin-4-ol and 1,5-dihydro-4 H -pyrazolo (3 , 4-d) pyrimidin-4-one:

As indicated above, it was unexpectedly found that topical application of allopurinol or its pharmaceutically acceptable salt is suitable for the treatment and prevention of LPS caused by MICs.

Thus, in one aspect, the invention relates to the use of allopurinol or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of LPS caused by therapy with a multipurpose kinase inhibitor.

In one embodiment, the medicament is in the form of a cream. Preferably, the cream is a hydrophilic cream.

In another embodiment, the medicament is for treating LPS caused by MIC Sorafenib, either alone or in combination with other agents.

In another embodiment, the medicament is for treating LPS caused by Sunitinib MICs, both alone and in combination with other agents.

Thus, the drug is suitable for the treatment of patients suffering from malignant neoplasm, preferably renal cell carcinoma, hepatic cell carcinoma, breast cancer, stromal tumors of the gastrointestinal tract (GIST), non-small cell lung cancer (NSCLC), melanoma and receiving MIK therapy as hell neoadjuvant or palliative. Examples of patients and therapies that cause LPS are discussed in the Background of the Invention.

An allopurinol-containing LPS medication is especially suitable for patients receiving or planning to receive sorafenib, sunitinib, or other MICs, either alone or in combination with other agents.

Local application of allopurinol provides effective treatment of the affected areas and prevents toxic effects and complications that systemic administration of allopurinol to patients with malignant neoplasms can cause. This avoids the negative impact on the therapy of malignant neoplasms.

Allopurinol is a compound poorly soluble in water and alcohol; practically insoluble in chloroform and in ether; it dissolves in dilute solutions of alkali metal hydroxides. It can be used in its native form, or instead, you can use a salt, such as sodium salt, to improve solubility in water.

In a preferred embodiment, the drug is in the form of a topical pharmaceutical composition for treating hands and feet, comprising allopurinol or a pharmaceutically acceptable salt thereof, together with at least one carrier material suitable for topical application.

In topical compositions used to treat LPS, allopurinol or its salts are usually in an amount of about 1 to 10%, in particular 1-8%, more specifically 1-6%, in particular 1 to 5%. Concentrations of about 1%, about 3% and about 8% are preferred.

A preferred range is from 2 to 5%, more preferably 2-4% of the total weight of the base composition. A content of about 3% gives good results and is particularly preferred. Unless otherwise indicated, all percentages are indicated as wt.% (Wt./mass.).

Pharmaceutical compositions suitable for topical application to the arms and legs, more preferably on the affected areas of the palms and feet, are, for example, creams, lotions, ointments, microemulsions, ointments, gels, emulsions, gels, pastes, foams, tinctures, solutions, patches, bandages and transdermal therapeutic systems. Most preferred are creams or emulsions-gels.

Creams or lotions are oil-in-water emulsions. Suitable oil bases are fatty alcohols, especially those containing from 12 to 18 carbon atoms, for example lauryl, cetyl or stearyl alcohol, fatty acids, especially those containing from 10 to 18 carbon atoms, for example palmitic or stearic acid, fatty acid esters, for example glyceryltricaprilocaprate ( neutral oil) or cetyl palmitate, liquid paraffins, for example isopropyl myristate, lanolin or beeswax and / or hydrocarbons, especially liquid, semi-solid or solid substances, or mixtures thereof, for example petrolatum oil (petrolatum, petroleum jelly) or paraffin oil. Suitable emulsifiers are surfactants having predominantly hydrophilic properties, such as corresponding nonionic emulsifiers, for example esters of fatty acids and polyalcohols and / or products of the addition of ethylene oxide to them, in particular, corresponding esters of fatty acids with (poly) ethylene glycol, ( poly) propylene glycol or sorbitol, in particular fatty acid residues containing from 10 to 18 carbon atoms, in particular, partial esters of glycerol and fatty acids or partial fatty acid and polyhydroxyethylene sorbitan fatty acids, such as polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tweens), and polyoxyethylene fatty alcohol ethers or fatty acid esters, fatty alcohol residues containing, in particular, from 12 to 18 carbon atoms and fatty acid residues, in particular 10 to 18 carbon atoms, such as polyhydroxyethylene glycerol ester of a fatty acid (e.g. Tagat S), or corresponding ionic emulsifiers, such as salts alkali metals sulfates of fatty alcohols, in particular having from 12 to 18 carbon atoms in the residue of a fatty alcohol, for example sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which are commonly used in the presence of fatty alcohols, for example cetyl alcohol or stearyl alcohol. Additives to the aqueous phase are, among others, anti-drying agents, for example, moisturizers, such as polyalcohols, such as glycerin, sorbitol, propylene glycol and / or polyethylene glycol, as well as preservatives, flavors, gelling agents, etc.

Ointments are water-in-oil emulsions containing up to 70%, but preferably from about 20% to about 50% of the water or aqueous phase. Suitable fatty phases are, in particular, hydrocarbons, for example paraffin oil, paraffin oil and / or hard paraffins, which, in order to improve the ability to bind water, preferably contain suitable hydroxyl compounds, such as fatty alcohols or their esters, for example cetyl alcohol or lanolin alcohols, or lanolin, or beeswax. Emulsifiers are corresponding lipophilic substances, for example, of the above, such as esters of sorbitol and fatty acids (Spans), for example sorbitan oleate and / or sorbitan isostearate. Humidifiers, such as polyalcohols, for example glycerin, propylene glycol, sorbitol and / or polyethylene glycol, as well as preservatives, flavorings, etc., are additives to the aqueous phase, among others.

Microemulsions are homogeneous systems based on the following four components: water, a surfactant, a non-polar or polar lipid, such as paraffin oil, natural oils, such as olive or corn oil, and alcohol or polyalcohol-containing lipophilic groups, for example 2-octyldodecanol, or ethoxylated glycerol, or polyglycerol esters. If desired, other additives can be added to the microemulsions. Microemulsions contain micelles or particles smaller than 200 nm in size and are spontaneously formed, stable, transparent or translucent systems.

Fatty ointments are anhydrous and contain, in particular, hydrocarbons, for example paraffin, paraffin oil and / or liquid paraffins, also natural or partially synthetic fats, such as glycerol esters of fatty acids, for example, coconut oil fatty acid triglycerides, or preferably hydrogenated oils, for example, hydrogenated peanut oil, castor oil or paraffins, also fragments of esters of fatty acids and glycerol, for example, glycerol mono- and distearate, as well as, for example, fatty alcohols that increase the ability to bind water, emulsifiers and / or additives indicated in the case of ointments.

In the case of gels, a distinction has been made between aqueous gels, anhydrous gels and gels with a low water content, which consist of swelling gelling materials. In particular, transparent hydrogels based on inorganic or organic macromolecules are used. The high molecular weight inorganic components having gelling properties are predominantly water-containing silicates, such as aluminum silicates, for example bentonite, magnesium and aluminum silicates, for example Veegum, or colloidal silicic acid, for example Aerosil. As organic substances with a high molecular weight, for example, natural, semi-synthetic or synthetic macromolecules are used. Natural and semi-synthetic polymers are obtained, for example, from polysaccharides containing a wide variety of carbohydrate fragments, such as cellulose, starch, tragacanth gum, gum arabic and agar-agar, gelatin, alginic acid and its salts, for example sodium alginate and its derivatives, such as lower alkyl celluloses, for example methyl or ethyl cellulose, lower carboxy or hydroxyalkyl celluloses, for example carboxymethyl or hydroxyethyl cellulose. Fragments of synthetic gelling macromolecules are, for example, corresponding substituted unsaturated aliphatic compounds such as vinyl alcohol, vinylpyrrolidine, acrylic or methacrylic acid.

Gels emulsions - also called "emulsions" - are local compositions combining the properties of a gel and an oil-in-water emulsion. Unlike gels, they contain a lipid phase, which, thanks to its ability to restore fat content, allows the composition to be rubbed, while direct absorption into the skin is perceived as a pleasant quality. In addition, everyone can observe increased absorption of lipophilic active ingredients. One of the advantages of emulsion gels over oil-in-water emulsions is the enhanced cooling effect that can be achieved by cooling due to the evaporation of an auxiliary alcohol component, if any.

Foams are applied, for example, from pressurized containers and they are liquid oil-in-water emulsions in the form of aerosols; unsubstituted hydrocarbons, such as alkanes, for example propane and / or butane, are used as a spraying agent. Hydrocarbons, for example paraffin oil, fatty alcohols, for example cetyl alcohol, fatty acid esters, for example isopropyl myristate and / or other paraffins, are used as the oil phase. As emulsifiers, mixtures of emulsifiers having predominantly hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens), and emulsifiers having predominantly lipophilic properties, such as sorbitol fatty acid esters (Spans) are used, among others. Standard additives such as preservatives, etc. are also used.

Tinctures and solutions generally have an ethanol base into which water can be added and to which, among others, polyalcohols, for example glycerol, glycols and / or polyethylene glycol, are added as humectants to reduce evaporation, and fat-reducing substances, such as esters of low molecular weight fatty acids and polyethylene glycol, propylene glycol or glycerol, in other words, lipophilic soluble substances in an aqueous mixture as substitutes for fatty substances removed from the skin with ethanol, and, if necessary spine, other auxiliaries and additives. Acceptable tinctures or solutions can also be applied as a spray using a suitable device. Due to problems with the solubility of allopurinol, in this case, the salt is more suitable for tinctures or solutions.

Transdermal therapeutic systems, especially those with local delivery of allopurinol, contain an effective amount of allopurinol, optionally in conjunction with a carrier. Suitable carriers include absorbable pharmacologically acceptable solvents to facilitate the penetration of the active ingredient through the skin. Transdermal delivery systems are, for example, patches comprising (a) a backing (support layer or film), (b) a base containing the active ingredient, optionally carriers and optionally (but preferably) a special astringent for attaching the system to the skin, and usually (c) a protective coating (removable thin film). The base (b) is usually present as a mixture of all components or may consist of separate layers.

All of these systems are well known to those skilled in the art. The manufacture of topical pharmaceuticals is, in a sense, effective in itself, for example, by dissolving or distributing allopurinol in the base or, if necessary, in part thereof.

The compositions may also include standard dermatological additives and adjuvants, such as preservatives, in particular paraben esters such as methyl paraben, ethyl paraben, propyl paraben, butyl paraben, or quaternary ammonium compounds such as benzalkonium chloride or formaldehyde donors such as imidazonidinyl ureas or alcohols, such as benzyl alcohol, phenoxyethanol, or acids such as benzoic acid, sorbic acid; acids or bases are used as excipients in a pH buffer; antioxidants, in particular phenolic antioxidants, such as hydroquinone, tocopherol and their derivatives, as well as flavonoids, or combined antioxidants, such as ascorbic acid, ascorbyl palmitate; flavorings; fillers such as kaolin or starch; pigments or dyes; UV protective agents; humectants, in particular glycerin, butylene glycol, hexylene glycol, urea, hyaluronic acid or their derivatives; anti-free radical agents such as vitamin E or its derivatives; penetration enhancers, in particular propylene glycol; ethanol; isopropanol; dimethyl sulfoxide; N-methyl-2-pyrrolidone; fatty acids / alcohols such as oleic acid, oleyl alcohol; terpenes such as limonene, menthol, 1,8-cineole; alkyl esters such as ethyl acetate, butyl acetate; ion pairing agents such as salicylic acid.

Additional features regarding acceptable local formulations are available in standard manuals such as Banker and Rhodes (Ed) Modern Pharmaceutics 4th ed. (2002) published by Marcel Dekker Inc .; Harry's Cosmeticology (2000), 8th Edition, Chemical Publishing Co .; Remington's Pharmaceutical Sciences 20th ed Mack Publishing Co. (2000) .

In a preferred embodiment, allopurinol is formulated into a cream, preferably an emollient base, the proposed emollient base is suitable for topical application to the skin, is practically non-toxic and provides a suitable carrier for allopurinol or a pharmaceutically acceptable salt thereof. A properly selected emollient base can also provide a small soothing effect by itself. In a special case, a moisturizer is the preferred base.

Emollients can be, for example, fatty alcohols, hydrocarbons, triglycerides, paraffins, esters, silicone oils and lanolin-containing products. Fatty alcohols are, for example, cetyl alcohol, octillauryl alcohol, stearyl alcohol and oleyl alcohol. Hydrocarbons include mineral oil, petroleum jelly, paraffin, squalene, polybutene, polyisobutene, hydrogenated polyisobutene, ceresin and polyethylene. Triglycerides are, for example, castor oil, capric / capric triglyceride, hydrogenated vegetable oil, sweet almond oil, wheat germ oil, sesame oil, hydrogenated cottonseed oil, coconut oil, wheat germ glycerides, avocado oil, corn castrozena, trihydric oil oil, shea butter, cocoa butter, soybean oil, mink oil, sunflower oil, safflower oil, Australian nut oil, olive oil, apricot kernel oil, oil hazelnuts and borage oil. Paraffins include, for example, carnauba wax, beeswax, cadella wax, Japanese paraffin, microcrystalline wax, jojoba oil, cetylester wax and synthetic jojoba oil. Esters include, for example, isopropyl myristate, isopropyl palmitate, octyl palmitate, isopropyl linoleate, benzoates of alcohols 12-15, cetyl palmitate, myristyl myristate, myristyl lactate, cetyl acetate, propylene glycol dicaprylate / caprate, decyloleate, stearyltearyltearyl-steralide Silicone oils are, for example, dimethicone (dimethylpolysiloxane) and cyclomethicone. Lanolin-containing products are, for example, lanolin, lanolin oil, isopropyl lanolate, acetylated lanolin, acetylated lanolin, hydroxylated lanolin, hydrogenated lanolin and lanolin wax.

In a preferred embodiment, allopurinol is treated by mixing it with a conventional commercial cream such as Bag Balm or Basiscreme DAC (Deutsches Arzneimittel codex).

The daily dosage of a topical composition, including allopurinol or its pharmaceutically acceptable salts, may depend on various factors, such as gender, age, weight and individual characteristics of the patient, as well as on the chemotherapy he receives or will receive, and the severity of LPS.

Local pharmaceutical compositions, for example, in the form of creams, emulsions, gels or gels, can be applied once, twice, or thrice a day, more frequent application is also possible, from 5 to 10 times a day, provided that the symptoms of LPS are eliminated or prevented . The dosage can be adjusted depending on the severity of the symptoms of LPS, or the courses or dosages of MIC therapy. It is recommended to apply with one fingertip.

The pharmaceutical composition of the invention is prescribed to patients already suffering from various stages of LPS or, as a prophylactic treatment, to patients predisposed to the development of LPS as a result of the MIC therapy they receive or plan to receive.

Reception can be increased shortly before, during and after chemotherapy, when the risk of developing LPS is higher, and can be reduced during periods of rest between courses.

The invention will be further illustrated by examples, which should not be construed as limiting the scope of the invention defined by the claims.

EXAMPLES

EXAMPLE 1

Obtaining a local composition, including allopurinol.

The composition was obtained by suspending the base of allopurinol (3% by weight of the total composition) in 5% water and then adding Basiscreme AC (92%) and mixing.

The composition of Basic DAC cream is as follows:

Glycerin monostearate: 4.0

Cetyl alcohol 6.0

Medium chain triglycerides 7.5

White Vaseline 25.5

Polyoxyethylene glycerol monostearate 7.0

Propylene glycol 10.0

Water 40.0

The resulting cream is transferred to suitable containers and stored. The cream is easily applied by the patient.

EXAMPLE 2

Palmar-plantar syndrome treatment

A male patient (65 years old) with advanced metastatic renal cell carcinoma (MRCC) was operated on and, after developing metastases, received Nexavar® (sorafenib) as a palliative therapy in reduced doses (200 mg 2 times a day). After 7 months, treatment was stopped due to LPS, fatigue, loss of appetite and diarrhea. An attempt to conduct palliative therapy of the third / second line was performed using Sutent® (sunitinib) in a reduced dosage of 37.5 mg daily for 1-28 days every 6 weeks.

During treatment with sorafenib, the patient developed LPS with extremely thick hyperkeratosis and soreness on the palms and feet, which did not disappear when the treatment regimen changed from sorafenib to sunitinib. In order to improve his condition and in order to prevent the cessation of therapy for malignant neoplasms, we started local treatment with the cream obtained in Example 1, which was applied 3 times a day.

Results: in the process of topical application of allopurinol, the symptoms of LPS almost completely disappeared, and sunitinib therapy was completed without any reduction in dosage or delayed treatment due to LPS. No toxic effects have been identified associated with topical use of allopurinol.

Surprisingly, after only one week of treatment with allopurinol, the symptoms of LPS reversed from stage 3 to stage 1 and 0 in most of the affected areas. The most significant was the disappearance of thick hyperkeratosis. Treatment with sunitinib and allopurinol cream was continued until therapy was discontinued due to tumor progression.

EXAMPLE 3

Treatment of palmar-plantar syndrome.

A male patient (74 years old) with advanced hepatic cell carcinoma (HCC) began receiving palliative therapy with sorafenib with an initially reduced dosage (200 mg 2 times a day). After 2½ months, he developed stage 1 LPS. He was treated with allopurinol cream as described in Example 1, and the symptoms of LPS disappeared after 7 days.

The dosage of sorafenib was increased to the recommended dose of 400 mg 2 times a day. No additional symptoms of LPS were detected despite the presence of other correctable side effects, such as diarrhea. The patient continued his treatment with sorafenib according to the planned schedule.

EXAMPLE 4

A patient (56 years old) with metastatic renal cell carcinoma (MRCC) was diagnosed with bone and lung metastases in August 2008. He was initially treated with intravenous administration of Torisel for 6 months. After the progression of metastases and nephrectomy of the right kidney, he was prescribed Sutent® (sunitinib) as a palliative therapy in a standard dosage of 50 mg daily for 1-28 days every 6 weeks.

During treatment with sunitinib, the patient developed LPS with keratosis (peeling and damage to the fingertips) and soreness on the palms and feet, which did not disappear after treatment with softening cream. In order to improve his condition and in order to prevent the cessation of therapy for malignant neoplasms, we started local treatment with the cream obtained in Example 1, which was applied 3 times a day.

Results: as a result of topical application of allopurinol, the symptoms of LPS almost completely disappeared, and sunitinib therapy was completed without any reduction in dosage or delayed treatment due to LPS. No toxic effects have been identified associated with topical use of allopurinol.

After only one week of treatment with allopurinol, the symptoms of LPS reversed from stage 2 to stage 1 and 0 in most of the affected areas. Treatment with sunitinib and allopurinol cream is still ongoing.

EXAMPLE 5

A 71-year-old patient with renal cell carcinoma, first diagnosed in 2001, underwent surgery. In 2005, she developed metastatic renal cell carcinoma (MRCC) (metastases to the liver and local) and, after the progression of metastases, she was treated with Nexavar® (sorafenib) as a palliative therapy (400 mg 2 times a day). The therapy was interrupted in September 2007 due to toxicity (LPS, diarrhea). Second-line palliative therapy was started with Sutent® (sunitinib) at a dosage of 50 mg daily for 1-28 days every 6 weeks. She had to be interrupted after a month due to even greater toxicity problems than in the case of Nexavar (edema, depression, allergies), and return to the Nexavar treatment (sorafenib), which was supplemented a month later with the allopurinol cream from Example 1 and loperamide for the treatment of LPS and diarrhea . Treatment made it possible to control LPS, but not diarrhea, for almost two years (November 2007 - September 2009). Treatment was interrupted after the progression of the malignant neoplasm. Then, for a short period of time, she received a course of Afinitor (everolimus) at 10 mg per day (September 2009 - March 2010), which was interrupted due to the lack of response to therapy and tumor progression. In the absence of alternative treatment, in March 2010, Nexavar (sorafenib) was resumed at a reduced dosage. After the development of LPS, one month later the treatment was supplemented with allopurinol cream.

Results: as a result of topical application of allopurinol, the symptoms of LPS almost completely disappeared and Nexavar therapy could continue. No toxic effects have been identified associated with topical use of allopurinol.

As shown in the examples, in four patients with advanced LPS, treatment with allopurinol facilitated the course of LPS and allowed completing the MIC therapy according to the planned schedule.

Claims (21)

1. A medicament for treating or preventing Palmar-Plantar Syndrome (LPS) caused by therapy with a multipurpose kinase inhibitor (MIC) containing a therapeutically effective amount of allopurinol or a pharmaceutically acceptable salt thereof. 2. The drug according to claim 1, where the palmar-plantar syndrome is caused by sunitinib. 3. The drug according to claim 1, where the palmar-plantar syndrome is caused by sorafenib. 4. The drug according to claim 1, where the drug is intended for topical use, preferably for local use on the skin of the hands or feet. 5. The drug according to claim 4, where the drug is a cream, preferably a hydrophilic cream. 6. The drug according to any one of claims 1 to 5, where the drug contains from about 1-10% by weight of the composition of allopurinol or its pharmaceutically acceptable salt, preferably from about 1% to about 8%, more preferably from about 2 to about 5% by weight. 7. The drug according to claim 1, where the drug contains approximately 3% by weight of the composition of allopurinol or its pharmaceutically acceptable salt. 8. The use of allopurinol or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of Palmar-Plantar Syndrome (LPS) caused by therapy with a multipurpose kinase inhibitor (MIC). 9. The use of allopurinol in the treatment or prevention of palmar-plantar syndrome (LPS) caused by therapy with a multipurpose kinase inhibitor (MIC). 10. The use of allopurinol in the treatment or prevention of palmar-plantar syndrome (LPS) caused by sunitinib. 11. The use of allopurinol in the treatment or prevention of palmar-plantar syndrome (LPS) caused by sorafenib. 12. A method of treating or preventing palmar-plantar syndrome (LPS) caused by therapy with a multipurpose kinase inhibitor (MIC) in a patient in need thereof, comprising administering to a patient a medicament containing a therapeutically effective amount of allopurinol or a pharmaceutically acceptable salt for treating or preventing palmar - plantar syndrome. 13. The method of claim 12, wherein the LPS is caused by sorafenib. 14. The method of claim 12, wherein the LPS is caused by sunitinib. 15. The method according to item 12, where the drug is applied topically to the skin. 16. The method according to clause 15, where the drug is applied topically to the skin of the hands or feet. 17. The method according to item 12, where the drug is a cream. 18. The method according to 17, where the drug is a hydrophilic cream. 19. The method according to item 12, where the drug contains from about 1% to about 10% by weight of the composition of allopurinol or its pharmaceutically acceptable salt. 20. The method according to claim 19, where the drug contains from about 1% to about 5% by weight of the composition of allopurinol or its pharmaceutically acceptable salt. 21. The method according to claim 20, where the drug contains approximately 3% by weight of the composition of allopurinol or its pharmaceutically acceptable salt.